1. Field of Invention
This invention relates to N-oxide and/or di-N-oxide derivatives of “dopamine receptor stabilizers/modulators” (examples of stabilizers are OSU6162 and ACR16), having improved therapeutic potential, improved oral bioavailability, improved side-effects profile, in particular with respect to decreasing the risk of eliciting a prolongation of the QT interval and thereby also decreasing the risk of eliciting Torsades de Pointes, and a longer duration of action, as well as pharmaceutical compositions comprising these compounds and suitable pharmaceutical carriers, methods of treating neurological and/or psychiatric diseases in a mammal using the drugs, and methods for preparing the drugs.
2. Background Art about N-Oxides/Di-N-Oxides
The N-oxides of certain morphinan derivatives are known in the prior art, e.g., Tiffany, U.S. Pat. No. 2,813,097, discloses 3-hydroxy-N-methyl-morphinan N-oxide and its utility as an analgesic. Tiffany, U.S. Pat. No. 2,813,098, discloses 3-methoxy-N-methylmorphinan N-oxide and its utility as an antitussive agent. Although it is stated that these N-oxides have a higher therapeutic index than the corresponding tertiary amines, there is no suggestion that the N-oxide of 3-hydroxy-N-methyl morphinan might have improved oral bioavailability relative to the parent compound.
Bartels-Keith, U.S. Pat. No. 3,299,072, discloses thebaine derivatives. These compounds have analgesic and/or narcotic antagonist activity. The reference claims the tertiary amines, the N-oxides, and various salts of the stated formula without distinguishing the N-oxides in any way. There is no mention of route of administration.
N-oxide derivatives of other non-morphinan analgesics have been reported. W. Graf, Swiss Pat. No. 481, 124.
K. Orzechowska, Arch. Immunol. Ther. Exp. 15(2), 290 (1967), and B. Bobranski and J. Pomorski, Arch. Immunol. Ther. Exp. 14(1), 121 (1966) report the preparation of the N-oxides of certain 1-alkyl-4-phenyl-4-acyloxy piperidine compounds. The N-oxide of 1-methyl-4-phenyl-4-propionoxypiperidine HCl exhibited analgesic activity equal to that of dolantin HCl, but of longer duration. Toxicity was also less.
The N-oxides of morphine and simple morphine derivatives such as codeine, hydromorphone (dihydromorphinone), and hydrocodone (dihydro codeinone), are well known, having been reported by, among others: M. Polonovski et al, Bull. Acad. Med. 103, 174 (1930); N. H. Chang et al, J. Org. Chem. 15, 634 (1950); B. Kelentei et al, Arzneimittel-Forsch. 7, 594 (1957); K. Takagi et al, Yakugaku Zasshi 83, 381 (1963) (Chem. Abs. 59: 9224b); L. Lafon, U.S. Pat. No. 3,131,185; M. R. Fennessy, Brit. J. Pharmacol. 34, 337 (1968); M. R. Fennessy, Eur. J. Pharmacol. 8, 261 (1969); and M. R. Fennessy, J. Pharm. Pharmacol. 21, 668 (1969). Morphine N-oxide is variously reported to be either less active or inactive as an analgesic but an effective antitussive, as well as having somewhat lower toxicity than morphine. There is no indication, however, that these N-oxides were ever administered orally, nor any suggestion that they might exhibit improved oral bioavailability.
Woods, Brit. Pat. No. 1,217,296, discloses the use of a combination of morphine N-oxide and amiphenazole as an analgesic composition. The combination is said to enhance the analgesic activity of morphine N-oxide while reducing the side-effects of both compounds.
Oxidative metabolism to an N-oxide which is excreted is among the many metabolic pathways which have been identified in mammals administered various tertiary amines. J. D. Phillipson et al, Eur. J. Drug Metab. Pharmacokinetics 3, 119 (1978), report that morphine and codeine are converted in part to the corresponding N-oxides by a guinea pig liver microsomal preparation, and also that these two drugs are partially metabolized to the N-oxides when administered to rats. T. Ishida et al, Drug Metab. Dispos. 7, 162 (1979), and T. Ishida et al, J. Pharmacobio-Dyn. 5, 521 (1982), report that oxycodone N-oxide is one of a number of identifiable metabolites found in the urine of rabbits administered oxycodone subcutaneously. While other metabolites were found in both free and conjugated forms, oxycodone-N-oxide was found only in the free, unconjugated form. The analgesic activity of oxycodone is believed to be due to the unchanged drug rather than the metabolites. S. Y. Yeh et al, J. Pharm. Sci. 68, 133 (1979), also report isolating morphine N-oxide from the urine of guinea pigs administered morphine sulfate.
Certain tertiary amine N-oxides are partially metabolized by reduction to the tertiary amine upon administration to test animals. R. L. H. Heimans et al, J. Pharm. Pharmacol. 23, 831 (1971) report that morphine N-oxide is partially reduced to morphine after administration to rats. T. Chyczewski, Pol. J. Pharmacol. Pharm. 25, 373 (1973), reports that the N-oxide of 1-methyl-4-phenyl-4-piperidinol propionate is partially reduced to the tertiary amine following administration to rabbits, mice, and rats. P. Jenner et al, Xenobiotica 3 (6), 341 (1973), report that nicotine-1′-N-oxide is partially reduced to nicotine in man after oral administration, but not after intravenous administration. Oral administration of nicotine-1′-N-oxide substantially avoids the first-pass phenomenon seen with oral nicotine. The reduction to nicotine which occurs in the lower gastrointestinal tract is believed to be by GI flora.
It is well established that N-oxidation of the aliphatic tertiary amine group(s) in the N-10 side chain of Phenothiazine antipsychotics agents is a major route of metabolism of these drugs in humans (Yeung, P. K., et al., J Pharm Sci, 1987. 76(10): p. 803-8; Marder, S. R., et al., Psychopharmacol Bull, 1989. 25(3): p. 479-82; Aravagiri, M., et al., Ther Drug Monit, 1990. 12(3): p. 268-76; Marder, S. R., et al., Psychopharmacol Bull, 1990. 26(2): p. 256-9; Marder, S. R., et al., Br J Psychiatry, 1991. 158: p. 658-65; Hubbard, J. W., et al., Br J Psychiatry Suppl, 1993(22): p. 19-24; Javorski, T. J. and M. S. Sardessai, Journal of Pharmaceutical Sciences, 1993. 82(3): p. 330-333; Midha, K. K., et al., Ther Drug Monit, 1993. 15(3): p. 179-89; Yeung, P. K., et al., Eur J Clin Pharmacol, 1993. 45(6): p. 563-9; Aravagiri, M., et al., Ther Drug Monit, 1994. 16(1): p. 21-9).
High plasma levels of N-oxide metabolites have been seen in humans for chlorpromazine, fluphena-zine, and trifluoroperazine. However, the true contribution of these metabolites to the clinical response has been investigated only in the case of fluphenazine. Fluphenazine N4-oxide was more strongly associated with side-effects than was the parent drug. Chlorpromazine N-oxide was, on the contrary, devoid of anti-dopaminergic effects. However, chlorpromazine N-oxide is converted to chlorpromazine in humans, and its metabolic profile is very similar to that of the parent drug. It is known that both clozapine N-oxide (Chang, W., et al., Prog Neuropsychopharmacol Biol Psychiatry, 1998. 22(5): p. 723-739) and olanzapine N-oxide (U.S. Pat. No. 6,352,984 B1) are metabolites of clozapine and olanzapine, respectively. It is also known that their corresponding N-oxides are prodrugs, generating clozapine and olanzapine, respectively.
The oral administration of many drugs will usually elicit a substantially lesser response as compared to an equal dose administered parenterally. This reduction in potency most commonly results from an extensive metabolism of the drug during its transit from the gastrointestinal tract to the general circulation. For example, the intestinal mucosa and the liver, through which an orally administered drug passes before it enters the systemic circulation, are very active enzymatically and can thus metabolize the drug in many ways.
When an orally administered drug is rapidly metabolized to an inactive or significantly less active form by the gastrointestinal system or liver prior to entering the general circulation, its bioavailability is low. In certain instances, this problem can be circumvented by administering the drug by another route. Examples of such alternative routes include nasal (propranolol), sublingual (nitroglycerin) and inhalation (cromolyn sodium). Drugs administered by these routes avoid hepatic and gut-wall metabolism on their way to the systemic circulation.
In some instances, the presystemic metabolism of certain orally administered drugs can be overcome by derivatization of the functional group in the molecule that is susceptible to gastrointestinal or hepatic metabolism. This modification protects the group from metabolic attack during the absorption process or first pass through the liver. However, the masking group must ultimately be removed to enable the drug to exert its maximum effect, and since the masking group is released into the body, it must be relatively non-toxic. This conversion may take place in blood or tissue. These types of masked drugs are usually referred to as prodrugs.
Background Art about Dopaminergic Regulation/Modulation
Dopamine is a neurotransmitter in the brain. Since this discovery, made in the 1950s, the function of dopamine in the brain has been intensely explored. To date, it is well established that dopamine is essential in several aspects of brain function including motor, cognitive, sensory, emotional and autonomous (e.g. regulation of appetite, body temperature, sleep) functions. Thus, modulation of dopaminergic function may be beneficial in the treatment of a wide range of disorders affecting brain functions. In fact, both neurologic and psychiatric disorders are treated with medications based on interactions with dopamine systems and dopamine receptors in the brain.
Drugs that act, directly or indirectly, at central dopamine receptors are commonly used in the treatment of neurological and psychiatric disorders, e.g. Parkinson's disease and schizophrenia. Currently available dopaminergic pharmaceuticals have severe side effects, such as extrapyramidal side effects and tardive dyskinesia in dopaminergic antagonists used as antipsychotic agents, and dyskinesias and psychoses in dopaminergic agonists used as anti-Parkinson's agents. Therapeutic effects are unsatisfactory in many respects. To improve efficacy and reduce side-effects of dopaminergic pharmaceuticals, novel dopamine receptor ligands with selectivity at specific dopamine receptor subtypes or regional selectivity are sought for. In this context, also partial dopamine receptor agonists, i.e. dopamine receptor ligands with some, but not full, intrinsic activity at dopamine receptors, are being developed to achieve an optimal degree of stimulation at dopamine receptors, avoiding excessive dopamine receptor blockade or excessive dopamine stimulation.
Compounds belonging to the class of substituted 3-(phenyl-N-alkyl)piperidines, 4-(phenyl-N-alkyl)piperazines and substituted 4-(phenyl-N-alkyl)piperidines have been previously reported (e.g. OSU6162 and ACR16). Among these compounds, some are inactive in the CNS, some display serotonergic or mixed serotonergic/dopaminergic pharmacological profiles, while some are full or partial dopamine receptor antagonists or agonists with high affinity for dopamine receptors.
A number of 4-phenylpiperazines and 4-phenyl-piperidine derivatives are known and described, for example Costall et al. European J. Pharm. 31, 94, (1975), and Mewshaw et al. Bioorg. Med. Chem. Lett., 8, 295, (1998). The reported compounds are substituted 4-phenyl-piperazines, most of them being 2-, 3- or 4-OH phenyl substituted and displaying DA autoreceptor agonist properties.
Fuller R. W. et al., J. Pharmacol. Exp. Therapeut. 218, 636, (1981) disclose substituted piperazines (e.g. 1-(m-trifluoromethylphenyl)pi-perazine) which reportedly act as serotonin agonists and inhibit serotonin uptake. Fuller R. W. et al Res., Commun. Chem. Pathol. Pharmacol. 17, 551, (1977) disclose the comparative effects on the 3,4-dihydroxyphenylacetic acid and Res. Commun. Chem. Pathol. Pharmacol. 29, 201, (1980) disclose the comparative effects on the 5-hydroxyindole acetic acid concentration in rat brain by 1-(p-chlorophenol)-piperazine.
Boissier J. et al., Chem. Abstr. 61:10691c, disclose disubstituted piperazines. The compounds are reportedly adrenolytics, antihypertensives, potentiators of barbi-turates, and depressants of the central nervous system. In addition, Akasaka et al. (EP 0675118) disclose bifenylderivatives of piperazines, which exhibits dopamine D2 receptor antagonism and/or 5-HT2 receptor antagonism.
A number of different substituted piperazines have been published as ligands at 5-HT1A receptors, for example Glennon R. A. et al. J. Med. Chem., 31, 1968, (1988) and van Steen B. J., J. Med. Chem., 36, 2751, (1993), Dukat M.-L., J. Med. Chem., 39, 4017, (1996). Glennon R. A. discloses, in international patent applications WO 93/00313 and WO 91/09594, various amines, among them substituted piperazines, as sigma receptor ligands. Clinical studies investigating the properties of sigma receptor ligands in schizophrenic patients have not generated evidence of antipsychotic activity, or activity in any other CNS disorder. Two of the most extensively studied selective sigma receptor antagonists, BW234U (rimcazole) and BMY14802, have both failed in clinical studies in schizophrenic patients (Borison et al, 1991, Psychopharmacol Bull 27(2): 103-106; Gewirtz et al, 1994, Neuropsychopharmacology 10:37-40).
The recent patent application entitled “Noncardiotoxic pharmaceutical compounds.” by Donald L. Barbeau (US) (Pub. No. 20060035863/Pub. Date: 16 Feb. 2006 Ser. No. 11,199,866/Filed Date: 9 Aug. 2005, U.S. class: 514/89; 546/21, International class: A61K 31/675; C07F 9/59, provisional application No. 60,600,699, filed on 11 Aug. 2004, provisional application No. 60,673,545, filed on 21 Apr. 2005), relates to novel noncardiotoxic compounds and pharmaceutical compositions useful in the treatment of a variety of dis-orders including the treatment of depression, allergies, psychoses, cancer and gastrointestinal disorders. In particular, that invention describes pharmaceutical compositions that mitigate life-threatening arrhythmias such as torsade de pointes based on the fact that the high plasma levels of the cardiotoxic hydroxylated metabolites are avoided by the use of a noncardiotoxic prodrug, which was designed to be noncardiotoxic in its own right. By circumventing the first pass secondary metabolism, those hydroxylated metabolites will only be formed in a much smaller concentration than would be the case when administering the active principle itself.
Even though N-oxides are mentioned in the patent of Barbeau (see above), the present invention is directed to N-oxides of a certain class of dopamine receptor stabilizers related to OSU6162 and ACR16. It was surprisingly found that some of the claimed compounds, beside their ability to stabilize DA receptors via a reductive bioactivation pathway, also have an effect of their own on the DA receptor. Also surprisingly, it was found that these prodrugs have a pharmacokinetic profile which decrease the risk of serious cardiovascular side-effects (e.g. QTc and Torsades de Pointes).